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Journal of Clinical Immunology

, Volume 30, Issue 5, pp 693–702 | Cite as

Involvement of the AIM2, NLRC4, and NLRP3 Inflammasomes in Caspase-1 Activation by Listeria monocytogenes

  • Jianghong Wu
  • Teresa Fernandes-Alnemri
  • Emad S. AlnemriEmail author
Article

Abstract

Infection with Listeria monocytogenes can cause meningitis and septicemia in newborn, elderly, or immunocompromised individuals. Pregnant women are particularly susceptible to Listeria, leading to a potentially fatal infection. Cytosolic Listeria activates the proinflammatory caspase-1 and induces the processing and secretion of interleukins IL-1β and IL-18 as well as caspase-1-dependent pyroptosis. This study elucidates the role of various inflammasome components of host macrophages in the proinflammatory response to infection with Listeria. Here, we have used macrophages from AIM2-, NLRC4-, NLRP3-, and ASC-deficient mice to demonstrate that AIM2, NLRC4, and NLRP3 inflammasomes as well as the adaptor protein ASC all contribute to activation of caspase-1 in Listeria-infected macrophages. We show that Listeria DNA, which escapes into the cytosol of infected macrophages, triggers AIM2 oligomerization, caspase-1 activation, and pyroptosis. Interestingly, we found that flagellin-deficient Listeria, like Francisella tularensis, is recognized primarily by the AIM2 inflammasome, as no caspase-1 activation or cell death was observed in AIM2-deficient macrophages infected with this Listeria mutant. We further show that prior priming of NLRC4-deficient macrophages with LPS is sufficient for Listeria-induced caspase-1 activation in these macrophages, suggesting that TLR4 signaling is important for activation of the AIM2 and NLRP3 inflammasomes by Listeria in the absence of NLRC4. Taken together, our results indicate that Listeria infection is sensed by multiple inflammasomes that collectively orchestrate a robust caspase-1 activation and proinflammatory response.

Keywords

Listeria monocytogenes NLRs inflammasome pyroptosis caspase-1 AIM2 innate immunity 

Notes

Acknowledgments

We thank Drs Junying Yuan (Harvard University) for anti-mouse caspase-1 antibody, Junji Sagara for antibody to mouse ASC, Eicke Latz for the immortalized NLRP3-KO, NLRC4-KO, and ASC-KO macrophages, Daniel Portnoy for Listeria strains, Howard Young for the J2 retrovirus-producing ψCREJ2 cell line and Maria Covarrubias for technical assistance with confocal microscopy and Charles Scott for critical reading of the manuscript. This work is supported by grants from the National Institute of Health (AG14357 and AR055398 to E.S.A.) and a grant from GlaxoSmithKline.

References

  1. 1.
    Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell. 2010;140:805–20.CrossRefPubMedGoogle Scholar
  2. 2.
    Ting JP, Lovering RC, Alnemri ES, Bertin J, Boss JM, Davis BK, et al. The NLR gene family: a standard nomenclature. Immunity. 2008;28:285–7.CrossRefPubMedGoogle Scholar
  3. 3.
    Schroder K, Tschopp J. The inflammasomes. Cell. 2010;140:821–32.CrossRefPubMedGoogle Scholar
  4. 4.
    Fernandes-Alnemri T, Yu JW, Datta P, Wu J, Alnemri ES. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature. 2009;458:509–13.CrossRefPubMedGoogle Scholar
  5. 5.
    Hornung V, Ablasser A, Charrel-Dennis M, Bauernfeind F, Horvath G, Caffrey DR, et al. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature. 2009;458:514–8.CrossRefPubMedGoogle Scholar
  6. 6.
    Burckstummer T, Baumann C, Bluml S, Dixit E, Durnberger G, Jahn H, et al. An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome. Nat Immunol. 2009;10:266–72.CrossRefPubMedGoogle Scholar
  7. 7.
    Roberts TL, Idris A, Dunn JA, Kelly GM, Burnton CM, Hodgson S, et al. HIN-200 proteins regulate caspase activation in response to foreign cytoplasmic DNA. Science. 2009;323:1057–60.CrossRefPubMedGoogle Scholar
  8. 8.
    Fernandes-Alnemri T, Yu J, Juliana C, Solorzano L, Kang K, Wu J, et al. The AIM2 inflammasome is critical for innate immunity against F. tularensis. Nature Immunol. 2010;11:385–93.CrossRefGoogle Scholar
  9. 9.
    Rathinam VA, Jiang Z, Waggoner SN, Sharma S, Cole LE, Waggoner L, et al. The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses. Nat Immunol. 2010;11:367–9.Google Scholar
  10. 10.
    Fernandes-Alnemri T, Wu J, Yu JW, Datta P, Miller B, Jankowski W, et al. The pyroptosome: a supramolecular assembly of ASC dimers mediating inflammatory cell death via caspase-1 activation. Cell Death Differ. 2007;14:1590–604.CrossRefPubMedGoogle Scholar
  11. 11.
    Pamer EG. Immune responses to Listeria monocytogenes. Nat Rev Immunol. 2004;4:812–23.CrossRefPubMedGoogle Scholar
  12. 12.
    Bielecki J, Youngman P, Connelly P, Portnoy DA. Bacillus subtilis expressing a haemolysin gene from Listeria monocytogenes can grow in mammalian cells. Nature. 1990;345:175–6.CrossRefPubMedGoogle Scholar
  13. 13.
    Smith GA, Marquis H, Jones S, Johnston NC, Portnoy DA, Goldfine H. The two distinct phospholipases C of Listeria monocytogenes have overlapping roles in escape from a vacuole and cell-to-cell spread. Infect Immun. 1995;63:4231–7.PubMedGoogle Scholar
  14. 14.
    Tsuji NM, Tsutsui H, Seki E, Kuida K, Okamura H, Nakanishi K, et al. Roles of caspase-1 in Listeria infection in mice. Int Immunol. 2004;16:335–43.CrossRefPubMedGoogle Scholar
  15. 15.
    Torres D, Barrier M, Bihl F, Quesniaux VJ, Maillet I, Akira S, et al. Toll-like receptor 2 is required for optimal control of Listeria monocytogenes infection. Infect Immun. 2004;72:2131–9.CrossRefPubMedGoogle Scholar
  16. 16.
    Kobayashi KS, Chamaillard M, Ogura Y, Henegariu O, Inohara N, Nunez G, et al. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science. 2005;307:731–4.CrossRefPubMedGoogle Scholar
  17. 17.
    Park JH, Kim YG, Shaw M, Kanneganti TD, Fujimoto Y, Fukase K, et al. Nod1/RICK and TLR signaling regulate chemokine and antimicrobial innate immune responses in mesothelial cells. J Immunol. 2007;179:514–21.PubMedGoogle Scholar
  18. 18.
    Kim YG, Park JH, Shaw MH, Franchi L, Inohara N, Nunez G. The cytosolic sensors Nod1 and Nod2 are critical for bacterial recognition and host defense after exposure to Toll-like receptor ligands. Immunity. 2008;28:246–57.CrossRefPubMedGoogle Scholar
  19. 19.
    Machata S, Tchatalbachev S, Mohamed W, Jansch L, Hain T, Chakraborty T. Lipoproteins of Listeria monocytogenes are critical for virulence and TLR2-mediated immune activation. J Immunol. 2008;181:2028–35.PubMedGoogle Scholar
  20. 20.
    Mosa A, Trumstedt C, Eriksson E, Soehnlein O, Heuts F, Janik K, et al. Nonhematopoietic cells control the outcome of infection with Listeria monocytogenes in a nucleotide oligomerization domain 1-dependent manner. Infect Immun. 2009;77:2908–18.CrossRefPubMedGoogle Scholar
  21. 21.
    Warren SE, Mao DP, Rodriguez AE, Miao EA, Aderem A. Multiple Nod-like receptors activate caspase 1 during Listeria monocytogenes infection. J Immunol. 2008;180:7558–64.PubMedGoogle Scholar
  22. 22.
    Mariathasan S, Newton K, Monack DM, Vucic D, French DM, Lee WP, et al. Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature. 2004;430:213–8.CrossRefPubMedGoogle Scholar
  23. 23.
    Mariathasan S, Weiss DS, Newton K, McBride J, O'Rourke K, Roose-Girma M, et al. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature. 2006;440:228–32.CrossRefPubMedGoogle Scholar
  24. 24.
    Franchi L, Kanneganti TD, Dubyak GR, Nunez G. Differential requirement of P2X7 receptor and intracellular K+ for caspase-1 activation induced by intracellular and extracellular bacteria. J Biol Chem. 2007;282:18810–8.CrossRefPubMedGoogle Scholar
  25. 25.
    Kim S, Bauernfeind F, Ablasser A, Hartmann G, Fitzgerald KA, Latz E, et al. Listeria monocytogenes is sensed by the NLRP3 and AIM2 Inflammasome. Eur J Immunol. 2010 (in press).Google Scholar
  26. 26.
    Meixenberger K, Pache F, Eitel J, Schmeck B, Hippenstiel S, Slevogt H, et al. Listeria monocytogenes-infected human peripheral blood mononuclear cells produce IL-1beta, depending on listeriolysin O and NLRP3. J Immunol. 2010;184:922–30.CrossRefPubMedGoogle Scholar
  27. 27.
    Yu JW, Fernandes-Alnemri T, Datta P, Wu J, Juliana C, Solorzano L, et al. Pyrin activates the ASC pyroptosome in response to engagement by autoinflammatory PSTPIP1 mutants. Mol Cell. 2007;28:214–27.CrossRefPubMedGoogle Scholar
  28. 28.
    Bauernfeind FG, Horvath G, Stutz A, Alnemri ES, MacDonald K, Speert D, et al. Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol. 2009;183:787–91.CrossRefPubMedGoogle Scholar
  29. 29.
    Wessells J, Baer M, Young HA, Claudio E, Brown K, Siebenlist U, et al. BCL-3 and NF-kappaB p50 attenuate lipopolysaccharide-induced inflammatory responses in macrophages. J Biol Chem. 2004;279:49995–50003.CrossRefPubMedGoogle Scholar
  30. 30.
    Blasi E, Mathieson BJ, Varesio L, Cleveland JL, Borchert PA, Rapp UR. Selective immortalization of murine macrophages from fresh bone marrow by a raf/myc recombinant murine retrovirus. Nature. 1985;318:667–70.CrossRefPubMedGoogle Scholar
  31. 31.
    Hornung V, Bauernfeind F, Halle A, Samstad EO, Kono H, Rock KL, et al. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol. 2008;9:847–56.CrossRefPubMedGoogle Scholar
  32. 32.
    Franchi L, Amer A, Body-Malapel M, Kanneganti TD, Ozoren N, Jagirdar R, et al. Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1beta in salmonella-infected macrophages. Nat Immunol. 2006;7:576–82.CrossRefPubMedGoogle Scholar
  33. 33.
    Miao EA, Alpuche-Aranda CM, Dors M, Clark AE, Bader MW, Miller SI, et al. Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1beta via Ipaf. Nat Immunol. 2006;7:569–75.CrossRefPubMedGoogle Scholar
  34. 34.
    Hornung V, Latz E. Intracellular DNA recognition. Nat Rev Immunol. 2010;10:123–30.CrossRefPubMedGoogle Scholar
  35. 35.
    Franchi L, Eigenbrod T, Munoz-Planillo R, Nunez G. The inflammasome: a caspase-1-activation platform that regulates immune responses and disease pathogenesis. Nat Immunol. 2009;10:241–7.CrossRefPubMedGoogle Scholar
  36. 36.
    Way SS, Thompson LJ, Lopes JE, Hajjar AM, Kollmann TR, Freitag NE, et al. Characterization of flagellin expression and its role in Listeria monocytogenes infection and immunity. Cell Microbiol. 2004;6:235–42.CrossRefPubMedGoogle Scholar
  37. 37.
    Franchi L, Eigenbrod T, Nunez G. Cutting edge: TNF-alpha mediates sensitization to ATP and silica via the NLRP3 inflammasome in the absence of microbial stimulation. J Immunol. 2009;183:792–6.CrossRefPubMedGoogle Scholar
  38. 38.
    Amer A, Franchi L, Kanneganti TD, Body-Malapel M, Ozoren N, Brady G, et al. Regulation of legionella phagosome maturation and infection through flagellin and host ipaf. J Biol Chem. 2006;281:35217–23.CrossRefPubMedGoogle Scholar
  39. 39.
    MacMicking J, Xie QW, Nathan C. Nitric oxide and macrophage function. Annu Rev Immunol. 1997;15:323–50.CrossRefPubMedGoogle Scholar
  40. 40.
    Yates RM, Hermetter A, Taylor GA, Russell DG. Macrophage activation downregulates the degradative capacity of the phagosome. Traffic. 2007;8:241–50.CrossRefPubMedGoogle Scholar
  41. 41.
    Via LE, Fratti RA, McFalone M, Pagan-Ramos E, Deretic D, Deretic V. Effects of cytokines on mycobacterial phagosome maturation. J Cell Sci. 1998;111(Pt 7):897–905.PubMedGoogle Scholar
  42. 42.
    Schaible UE, Sturgill-Koszycki S, Schlesinger PH, Russell DG. Cytokine activation leads to acidification and increases maturation of Mycobacterium avium-containing phagosomes in murine macrophages. J Immunol. 1998;160:1290–6.PubMedGoogle Scholar
  43. 43.
    Tsang AW, Oestergaard K, Myers JT, Swanson JA. Altered membrane trafficking in activated bone marrow-derived macrophages. J Leukoc Biol. 2000;68:487–94.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Jianghong Wu
    • 1
    • 2
  • Teresa Fernandes-Alnemri
    • 1
    • 2
  • Emad S. Alnemri
    • 1
    • 2
    Email author
  1. 1.Department of Biochemistry and Molecular BiologyThomas Jefferson UniversityPhiladelphiaUSA
  2. 2.Kimmel Cancer CenterThomas Jefferson UniversityPhiladelphiaUSA

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